SLIDE 1
QUESTION #1:
The percent of pancreatic cancers that harbor potentially
“actionable” alterations (for which there is an FDA approved therapy [in pancreatic cancer OR other disease types]) is:
A.
3 – 5%
B.
10%
- C. 25%
- D. 40%
CASE 1: GENOMIC ANALYSIS AND MANAGEMENT OF METASTATIC PANCREATIC - - PowerPoint PPT Presentation
CASE 1: GENOMIC ANALYSIS AND MANAGEMENT OF METASTATIC PANCREATIC - - PowerPoint PPT Presentation
CASE 1: GENOMIC ANALYSIS AND MANAGEMENT OF METASTATIC PANCREATIC CANCER WITH AN ACTIONABLE ABERRATION SAMANTHA ARMSTRONG MD AND MICHAEL J. PISHVAIAN MD PHD QUESTION #1: The percent of pancreatic cancers that harbor potentially
SLIDE 2
SLIDE 3
QUESTION #1:
The percent of pancreatic cancers that harbor potentially
“actionable” alterations (for which there is an FDA approved therapy [in pancreatic cancer OR other disease types]) is:
A.
3 – 5%
B.
10%
- C. 25%
- D. 40%
Pishvaian, et al, Clinical Cancer Research, 2018; Heeke, et al, JCO Precision Oncology, 2018; Aguirre, et al, Cancer Discovery, 2018; Witkiewicz, et al, Nat Commun, 2015; Lowery, et al, Clinical Cancer Research, 2017; Waddell, et al, Nature, 2015; Bailey, et al, Nature, 2016; Biankin, et al, Nature, 2012; Collisson, et al, Nat Med, 2011
SLIDE 4
HISTORY OF PRESENT ILLNESS
Previously healthy 51 year old female presented with
abdominal pain in 2014
No medical or surgical history No tobacco or ETOH use Family history: father with lung cancer
SLIDE 5
DIAGNOSIS
CT Scan (and a subsequent
MRI/MRCP) showed a 2.9 x 2.6cm pancreatic head mass encasing the SMA
EUS-FNA pathology: well-
differentiated adenocarcinoma
Diagnosis: locally advanced
unresectable pancreatic adenocarcinoma
Image From Uptodate.comI
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TREATMENT TIMELINE
Frontline FOLFOX 12/2014 - 10/2016 Held oxaliplatin after Cycle 6 for neuropathy Incorporated SBRT to the mass in 03/2015 October, 2016 restaging scan: large right ovarian tumor
(12 x 10 x 12cm)
Resected in 11/2016 – pathology consistent with a metastasis from
the pancreatic primary Reinitiated FOLFOX 11/2016 Oxaliplatin stopped after only 4 additional cycles for an allergy
SLIDE 7
QUESTION #2:
Is the presence of a germline BRCA1/2 mutation in pancreatic
cancer know to be:
A.
Prognostic
B.
Predictive of a response to platinum-based therapy
- C. Both A and B
- D. Neither A nor B
SLIDE 8
QUESTION #2:
Is the presence of a germline BRCA1/2 mutation in pancreatic
cancer known to be:
A.
Prognostic
- B. Predictive of a response to platinum-based therapy
- C. Both A and B
- D. Neither A nor B
Golan, et al, BJC, 2014; Pishvaian, et al, JCO PO, manuscript in press, 2019
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MOLECULAR PROFILING OF THE METASTASIS
BRCA1 & BRCA2 non-mutated ATM mutation in exon 25 p.L1238fs KRAS mutation in exon 2 p.Gt2D SMAD4 mutation in exon 10 p.V387fs MET mutation in exon 2 p.P164A MS-stable Total mutational burden: 10 mutations/Mb
SLIDE 10
QUESTION #3:
The most common potentially “actionable” alteration in
pancreatic cancer is a (an):
A.
KRAS mutation
B.
BRCA1 or -2 mutation
C.
ATM mutation
- D. Defect in mismatch repair (MMR deficient/MSI-high)
E.
NTRK fusion
SLIDE 11
QUESTION #3:
The most common potentially “actionable” alteration in
pancreatic cancer is a (an):
A.
KRAS mutation
B.
BRCA1 or -2 mutation
- C. ATM mutation – 6.2% across multiple publications
- D. Defect in mismatch repair (MMR deficient/MSI-high)
E.
NTRK fusion
Pishvaian, et al, Clinical Cancer Research, 2018; Heeke, et al, JCO Precision Oncology, 2018; Aguirre, et al, Cancer Discovery, 2018; Witkiewicz, et al, Nat Commun, 2015; Lowery, et al, Clinical Cancer Research, 2017; Waddell, et al, Nature, 2015; Bailey, et al, Nature, 2016; Biankin, et al, Nature, 2012; Collisson, et al, Nat Med, 2011
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TREATMENT TIMELINE - CONTINUED
Transitioned to maintenance capecitabine 2/2017-6/2018 February, 2018 restaging scan: prepubic soft tissue mass (3.2 x 2.4 cm)
Suprapubic metastasectomy 3/15/2018 May, 2018 restaging scan showed pulmonary metastatic disease
SLIDE 13
TREATMENT TIMELINE - CONTINUED
Phase I trial of carboplatin plus niraparib 6/2018-8/2018
No benefit: August, 2018 restaging scan showed an enlarged
cervix, and a pelvic exam revealed a 4 cm cervical lesion Radiation to the cervical metastasis 9/2018 Gemcitabine plus nab-paclitaxel 11/2018-1/2019 At progression enrolled in a Phase I trial of irinotecan,
veliparib and the ATR inhibitor VX-970
Disease stable on trial through 6 months
SLIDE 14
IMPORTANCE OF GENOMIC SEQUENCING
Identify therapeutically relevant alterations in ~25% of PDACs
The majority of mutations identified are in the DNA damage
response and repair (DDR) genes DDR mutations render cells more sensitive to DNA damage Classically BRCA1/2 mutations respond to platinums and PARPi But…..not all DDR mutations are the same Research needed to identify how to treat different mutations
Pishvaian, et al, Clinical Cancer Research, 2018; Heeke, et al, JCO Precision Oncology, 2018; Aguirre, et al, Cancer Discovery, 2018; Witkiewicz, et al, Nat Commun, 2015; Lowery, et al, Clinical Cancer Research, 2017; Waddell, et al, Nature, 2015; Bailey, et al, Nature, 2016; Biankin, et al, Nature, 2012; Collisson, et al, Nat Med, 2011
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ATM MUTATIONS IN PDAC
ATM’s Function: Cell cycle checkpoint kinase Regulate downstream proteins Respond to DNA damage for
genome stability
ATM is one of the most commonly
mutated DDR genes in PDAC
Somatic mutations 2 - 18% Germline mutations 1 - 34%
Armstrong et al, Manuscript in Press, Molecular Cancer Research
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THERAPEUTIC SIGNIFICANCE OF ATM MUTATIONS
Uniquely sensitive to radiation therapy As seen in this case - prolonged control with SBRT Unlike BRCA1/2 mutations, ATM mutations are not always
responsive to platinum agents and PARP inhibitors
As seen in this case - rapid progression on platinum + a PARPi Synthetic lethality with an ATR inhibitor in the context of an ATM
mutation
Armstrong et al, Manuscript in Press, Molecular Cancer Research; Blackford and Jackson, Molecular Cell 66, June 15, 2017
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